Horton was attending a meeting of a UN Commission on Women's and Children's Health in Dar es Salaam and witnessed an interesting performance by Hamadoun Touré, Secretary General of the International Telecommunication Union. Touré (says Horton) "has a reputation for being blunt and outspoken. He surpassed himself last week." Toure stated: “There is more corruption in the G8 countries than in the whole of Africa.... We are just running away from the problem.” WHO Director-General Margaret Chan and Commission co-chair Jakaya Kikwete both jumped in to try to repair the damage, lest the rich countries think that the UN was not sufficiently grateful for their donations. Horton described their intervention as an attempt "to pull their colleague back from the brink of professional suicide....But Touré had a point too. And most of us in the room knew it." (The Health Care Renewal folks found it instructive that apparently, telling the truth at a meeting of a health-related UN commission is considered "professional suicide.")

Former Afghan finance minister Ashraf Ghani freely that corruption among Afghan officials is serious and rampant, but he then objected that it's disingenuous for the US to point fingers: "One [type of corruption] that is legal, and that's the U.S. corruption because it's a system of slicing of the pie. So, out of a dollar of civilian aid only 10 cents gets to be spent in Afghanistan, out of military aid only 30 cents gets to be spent in Afghanistan. This is a contracting system that's gone haywire. There is now security development NGO complex in Washington that's as powerful as the old military industrial complex and this needs to be reformed."

At least on the military side, I believe that Mr. Ghani is referring to what DC insiders call the "Beltway Bandits," a nested set of contractors and subcontractors. The government grants aid to a country like Afghanistan, and the money is awarded to a contractor. But that contractor seems incapable of actually sending the aid to where it is needed. Instead it makes a deal with a subcontractor. And that subcontractor makes a deal with another subcontractor. Each layer takes its cut of profit. By the time you get down through 5 or 6 layers, then maybe a small fraction of what Congress approved actually ends up in Afghanistan. And of course all those layers in the US make generous campaign donations to key Congresspeople, to be sure their little gravy train continues to roll on.

So powerful Afghans see how we do it in the US of A and then they decide to take their cut as well--and we rant and rave about "corruption" and threaten to cut off all future aid if they don't behave. Doesn't the Bible say something about complaining about the mote in someone else's eye and ignoring the beam in one's own?

And what does this have to do with medicine and the drug industry, one might wonder. Health Care Renewal has a consistent theme about how corporate leaders in health care (not just in pharmaceuticals) never seem to be held accountable, and can rake off millions in salaries while the organizations they head are going to pot. They provide numerous examples of lack of accountability at the CEO level. Therefore a recent Huffington Post piece by reporter Ricardo Alonso-Zaldivar is right up their alley:http://www.huffingtonpost.com/2011/05/31/feds-target-execs-health-fraud_n_868924.html

The post covers the renewed interest among Federal prosecutors to go beyond fining drug companies found guilty of fraud hundreds of millions of dollars, when in the past this seems never to have moderated their later behavior and the same fraudulent activity happens over and over. The Feds are starting to threaten criminal charges against the CEOs of these companies. The first target has been Howard Solomon of Forest Laboratories, who allegedly presided over behavior that led Forest to settle with the Feds for $313M. The company was said to have deliberately ignored an FDA warning about an unapproved thyroid drug, marketed an antidepressant approved only for adults for child use, and misled FDA inspectors doing a quality check at one of their plants. Solomon is now threatened with what the industry calls the "death penalty," banning Solomon permanently from doing business with the Federal government.

These threats to go after CEOs personally have gotten the attention of an industry that has traditionally treated hundred-million-dollar fines with a ho-hum. Forest is actively fighting Solomon's ban and corporate lawyers are threatening to fight the Feds in court and try to overturn the legal basis for these prosecutions.

To summarize: when people with the wrong color skin who wear the wrong sorts of clothes on the wrong side of the world try to take home some extra cash, it's corruption and we're all against it. When US CEOs use their power to take home multimillion-dollar paychecks even when running their firms into the ground and defrauding taxpayers, and their corporate boards (made up of similarly compensated bigshots) aid and abet this behavior and even justify it by claiming that the only way to get corporate "talent" is to pay big bucks for it, and all of the above pay off Congress, that, of course, is not corruption--it's the American way.

This German team led by Dr. Gisela Schott set out to update us about the influence of drug company sponsorship of clinical trials on the reliability of the published outcomes. They reviewed two important systematic reviews both published in 2003, and then surveyed the literature from when those studies left off until 2009, to see what the more recent studies showed. They identified 57 published studies that compared industry funded trials to those funded by other sources, or that were otherwise relevant.

Overall they replicated the results of the earlier systematic reviews, that there's a clear association between industry funding a trial and the results turning out positive for the company's drug. Again they demonstrated that this is unlikely to be due to poorer quality of the methodology of the industry trial.

They then tried to drill down a bit to see why this is the case. They noted that many unfavorable studies (possibly half) are not published, and many positive studies tend to be published multiple times. (I suppose, on average, that makes it all okay.) There is a considerable bias in what results are included in published work, with repeated evidence that adverse drug reactions are simply buried whenever and however possible. Despite the rise of clinical trial registries during the years covered by this new study, and industry group policies promising compliance with the journals' requirements that trials be registered, there are still industry-sponsored trials that are not being registered, and many "registered" trials are registered with key data missing.

The problems do not appear to be completely outside the controls of the journal editors, and the authors note the conflicts of interest that journals face when they depend on reprint and advertising sales to drug companies. The authors make a proposal that seems long overdue--that journals should be required to publish detailed financial statements annually. As I explained in HOOKED, the balance sheets of medical journal publishers were at the time that I wrote one of the hardest-to-locate (actually, in most cases, impossible to locate) data points in the whole business of the medicine-Pharma interface.

The other problem with journals is well illustrated by a separate article by Emerson and colleagues (subscription required; hat tip to Primary Care Medical Abstracts for this citation). These folks did a sneaky number on reviewers for a couple of orthopedics journals (though with prior consent). They concocted a fictitious trial and sent a manuscript for review. They also planted a few small errors in the Methods section of the manuscript, though by most standards the overall quality of the study would be graded as excellent. In half the cases, the results were shown as positive; in the other half everything else about the study was the same, but the results were negative.

Emerson and colleagues found that the positive version was recommended for publication 97% of the time but the negative version only 80% of the time. The reviewers were more likely to pick up on the planted errors if they were sent the negative version of the study, and if sent that version, they rated the overall methodologic quality lower. In short, reviewers of these journals were biased against negative and in favor of poisitive studies, and I doubt very much that this is somehow unique to orthopedics. Bottom line: when we look for reasons that negative drug studies are suppressed, we have to look both at industry manipulation and also at the inherent biases of journal reviewers and editors.

Saturday, May 28, 2011

As reported by JoNel Aleccia for MSNBC--http://www.msnbc.msn.com/id/43187290--the anti-smoking pill, Chantix (varenicline), manufactured by Pfizer, appears to have been responsible for many more suicides than previously reported (a total of perhaps 150, or double what had been known). But these reports were missed until recently when unearthed by the non-profit Institute for Safe Medication Practices. Thomas J. Moore, chief scientist on the ISMP review, called this a "major breakdown in safety surveillance."

There are two FDA reporting mechanisms for adverse drug reactions, one for routine and the other for more serious events. The FDA said that they became aware that Pfizer was sending its reports of suicides and other major events for Chantix through the same channel where it reported such minor side effects as nausea, meaning that the important stuff got lost among 26,000 reports of relatively minor reactions. Pfizer said that they promptly did what the FDA told them to do and so they were not at fault. Both basically said it was no big deal since, based on the earlier reports, Chantix already carries a black box warning that mentions suicide. (Critics of the drug say it is a big deal; that something about this drug seems to cause at least a few people with no history of violence to unexpectedly act in destructive ways.)

Now, I would like to give Pfizer (and the FDA) the benefit of the doubt on this one. I usually go by the adage that if conspiracy and incompetence are two possible explanations for what happened, the latter is much more likely than the former.

But something nags at the back of my mind--a story I related in HOOKED. During the mid-1990s, Wyeth-Ayerst was heavily marketing, and making huge profits from, the diet pill combo known as Fen-phen. The storm clouds gathering on their horizon were increasing reports of serious heart and lung disease among users of these drugs. When internal company documents were released as part of later lawsuits, a pattern emerged that suggested that the company had followed a deliberate policy in reporting adverse reactions to the FDA. Instead of reporting by the wrong channel, Wyeth-Ayerst set about concealing the serious reactions by seeking out any minor reaction that the same patient might have suffered. For example, if a patient with heart valve damage severe enough to require open-heart surgery also had reported some constipation, the company headed the report "Constipation" in big letters and added the heart valve issue as far lower down, in the smallest print, that they could. That way the company could claim legally that it had never failed to report a single side effect to the FDA, while assuring that overworked FDA reviewers had the least chance of picking up on the really serious stuff.

So, given that there's a history of drug companies manipulating the FDA reporting system to conceal serious adverse reactions of profitable drugs, is it completely possible to trust Pfizer's innocence in this matter? And for that matter, is it realistic to imagine that with all the technical staff, legal talent, etc. that a company as big as Pfizer has at its fingertips, that no one knew what were the proper channels for reporting serious adverse effects? I'm just asking.

I want briefly to summarize their list, then look more closely at the role of industry marketing.

Drs. Fuchs and Milstein begin by noting how out of line health care costs are in the US compared to comparable wealthy nations, without any discernible health advantage in exchange; and also how much money is now spent on ineffective interventions (they estimate at least $640B annually, more than enough to pay for all conceivable costs associated with extending insurance coverage to all Americans who now lack it). So why are we not able to save that money and redirect it to more useful purposes? Fuchs and Milstein's Enemies List:

Physicians: Don't want to give up money; fear standardization and giving up clinical autonomy that seems to go along with serious cost control

Academic health centers: assume that they cannot cut costs and still effectively teach and do research; thus forgo important opportunities to teach tomorrow's physicians a cost-effective approach

Industry: Often has the most to lose as system inefficiencies spell profits for them

Now, at first glance, it seems that industry enters into this mix in two places: by opposing efficiencies that cut into their sales, and by lobbying legislators. But a careful review of the whole list shows other opportunities for commercial marketing of drugs and devices to contribute to the present impasse. For example, why are the media so prone to spread hype and misinformation among the public about health issues? Could their heavy reliance on industry advertising (how many ads in the typical hour of TV end with "ask your doctor...") tilt their news and editorial policies? Why is the public so opposed to cost containment that ultimately is in the public interest--could this have anything to do with the way industry generously bankrolls patient-advocacy groups?

Fuchs and Milstein's concluding point should be no surprise to any readers of this blog who have followed my efforts to refocus attention on the ethical demands of professionalism in medicine: "There is not much physicians can do directly to change the behavior of ... other stakeholders, but physicians are the most influential element in health care. The public's trust in them makes physicians the only plausible catalyst of policies to accelerate diffusion of cost-effective care. Are U.S. physicians sufficiently visionary, public-minded, and well led to respond to this ethical imperative?"

Thursday, May 26, 2011

I've been very remiss in the past by not doing more to publicize the great conferences put on by the PharmedOut folks at Georgetown University. The conference coming up next month looks wonderful and I'm bummed that I'll personally be unable to attend. Please read all about it at:www.pharmedout.org/2011Conference.htm

There is a great lineup of excellent speakers, many of whom will be familiar names to any readers of this blog. The theme is the very important one: "Pharma Knows Best? Managing Medical Knowledge."

Sunday, May 22, 2011

A recent article in JAMA (subscription required) was called to my attention because it cites Don Light's and my Inverse Benefit Law (see http://brodyhooked.blogspot.com/2011/03/synthesis-why-drug-industry-tries-to.html). The article is outstanding in collecting several extremely important points within a mere two pages of discussion. I have a couple of quibbles with it (not surprising that they could not cover everything I wanted them to in just two pages), so I hope my quibbles will be somewhat instructive set along side the article itself.

Benjamin Djulbegovic, doing evidence-based medicine and health outcomes research at U. South Florida, and Ash Paul of Bedfordshire, UK team up to make roughly the following points (though the entire article deserves to be read carefully):

We want to know, for good medical practice, about effectiveness (does something work in real life practice?) and cost-effectiveness (is it worth the cost, considering other alternatives?) but usually we have to settle for data on efficacy only (could it possibly work based on evidence gathered in a select population under more or less unreal conditions?).

There's an inherent uncertainty in extrapolating from efficacy data to effectiveness. There's no technical fix for this uncertainty. We must make clinical and policy decisions while frankly aware of this.

Reliance on efficacy data and the absence of real effectiveness data leads to two serious problems--indication creep and prevention creep. We've discussed both in this blog at length. Indication creep is using a drug good for some things for other things for which it is not as good and where it poses risks of adverse reactions. (That's what the Inverse Benefit Law is mostly about.) Prevention creep is using a test that is helpful in some circumstances in other circumstances where it's guaranteed to generate too many false positives to be useful.

Indication and prevention creep between them drive up the costs of health care--Djulbegovic and Paul agree with what I think are the best available fiugures that about 30% of current health spending in the US goes to purchase "creepy" interventions that do not help patients. This poses a serious barrier to real cost containment.

So far so good, so how could one quibble? Well, this blog is primarily about how the pharmaceutical industry and the medical profession, between them, create serious ethical problems through their current, dysfunctional way of interacting. Djulbegovic and Paul are hardly blind to the role of Pharma in indication creep (in particular) and mention it in two places that I could see. But they also say the following: "While various mechanisms can lead to indication creep, ... at its core indication creep represents a shift from efficacy to effectiveness in an attempt to tailor research evidence to individual patients."

I interpret the "at its core" as follows: What is mostly going on in indication creep is physicians' desire to treat individual patients based on the best available evidence. When such evidence is flawed--specifically, based on efficacy rather than effectiveness data--physicians resolve the resulting uncertainty in favor of "treat" vs. "don't treat." (Surprise! American physicians are much more terrified of failing to do something they could do, instead of doing something that in the end turns out to be useless or even harmful.) This leads occasionally to harm to individual patients and even more often, to wasted resources. But the culprit is at root a conceptual one, physicians relying on efficacy data for effectiveness applications.

This conclusion makes good sense of your day job is teaching and doing research in evidence-based medicine. But I have to quibble with the suggestion (if I am reading it right) that the most important synapse in this neural mechanism is within the brains of physicians. We need to ask first why there is so much efficacy data and so little effectiveness data, and the answer is to be found in the disproportionate share of research funding coming from the drug industry, as well as that industry's backroom efforts to derail the new movement toward comparative effectiveness research and especially any cost-effectiveness research that might influence Federal policy (http://brodyhooked.blogspot.com/2009/05/stealth-campaign-to-shanghai-ce.html). Next we need to ask where physicians get the "evidence" that leads to so much indication creep, and the answer is to be found both in docs' reliance on industry marketing as so-called "education," and also in the systematic way that the industry distorts the medical literature by data suppression and manupulation (too many prior blog posts to even begin to list).

So, you reply, am I claiming that docs' thinking processes have nothing to do with this at all and we are all being led by the nose by Pharma? No, that's exactly the point. As I have said numerous times before, Pharma marketing hardly ever invents stuff out of whole cloth; they usually manage to grab ahold of something physicians are already thinking, and then turn it to their financial advantage. So yes, physicians are prone to do too much instead of too little, and they are prone to extrapolate from efficacy data to clinical practice on noncomparable patients. But were it not for the Pharma marketing juggernaut of roughly $57B annually in the US, EBM gurus like Djulbegovic and Paul would have a much easier time educating us about these dangers and perhaps even reforming actual practice. As it is, lots of luck.

There is one other person left out of their equation--the patient. Did physicians become fearful of doing too little in a social vacuum? Did physicians decide to extrapolate efficacy data beyond its proper limits just to have some fun? Or have American patients repeatedly demanded this style of care? And have Pharma companies systematically taken advantage of that public attitude to supplement their marketing, both in direct-to-consumer ads and in their funding of "astroturf" patient advocacy? Again we need to remember Applbaum's critical concept of controlling the "marketing channels" (http://brodyhooked.blogspot.com/2010/06/how-does-drug-industry-exert-power.html). Successful drug companies never market their wares in one single way; they are masters at making a set of apparently disconnected bits of marketing all fall into place in one grand pattern to influence medical thought down to its core. If we ignore the scope and importance of that influence we'll never get to the excellent reforms that Djulbegovic and Paul call for.

Djulbegovic B, Paul A. From efficacy to effectiveness in the face of uncertainty: indication creep and prevention creep. JAMA 305:2005-6, May 18, 2011.

Friday, May 20, 2011

A while ago we heard that the Massachusetts House had passed a bill to repeal the gift ban that was enacted as part of that state's health reform efforts (you know, the thing that then-Gov. Mitt Romney didn't do), under pressure from the combined Pharma and restaurant lobbies. I was waiting to do a blog post until I heard what the state Senate had to say, as last year, a similar bill was passed by the House and then died. But this humorous, consumer-oriented website--http://pharmawithachanceofmeatballs.tumblr.com/-- is such a nice summary that I felt obligated to pass it along (thanks to PostScript for alerting me).

If this rendition is true, then the sneaky Pharma folks are not only pushing to repeal the ban on gifts, on the basis that it's hurting the Mass. restaurant business in a time of recession (a claim that seems now to have been decisively refuted, by the way). They also are using this as cover to repeal the part of the law that mandates reporting of gifts to physicians, even though that presumably has no direct impact on restaurant business.

Most of the recent settlements we've reviewed in previous posts have to do with off label marketing. This case is more interesting because the Federal allegations are for direct kickbacks paid to physicians to prescribe the drug. Specifically, it is alleged, docs were sent to conferences at upscale resorts at company expense as a quid pro quo for prescribing. The company, as usual, says it did nothing wrong.

After the hundreds-of-millions settlements from some of the big guys recently, I almost did not list this one at all, as $44M seems to be chump change in this area.

Wednesday, May 11, 2011

Thanks to Dr. Barney Carroll, who in turn apparently knows a mole somewhere within the pharmaceutical marketing industry, I was provided with a copy of the brochure for the "2nd KOL Relationship Summit," to be held in Philadelphia on August 9-10. But the sponsor, "exlpharma," is hardly keeping it a secret, and you can look for yourself:http://www.exlpharma.com/events/2nd-kol-relationship-summit

For those of you who may have started reading this blog last week, "KOL" stands for "key opinion leader," which is drug industry-ese for a shill--a physician, often an academic physician, who's respected in her field and who, if you can bribe them to transmit your marketing message, is likely to sway her fellow physicians. But of course such crude terms as "shill" and "bribe" do not appear anywhere in the brochure, which explains:

"The 2nd KOL Relationship Summit helps pharmaceutical, medical device, and biotechnology companies, whether large or small, establish a reliable method of identifying, mapping, recruiting, and communicating with both global and local KOLs . Attendees will learn how to drive the success of a specific drug or medical device, educate physicians, and maintain a balance with compliance and business objectives. As well, this event explains current rules and regulations impacting the industry surrounding KOLs, how to utilize social media in KOL development and communication, suggest methods of best practices for determining fair market value, and bridging KOL relationships within a company to enhance team dynamics."

You know doubt want to know how to do all this, so you will not kick at paying the registration fee of $1695 in advance, or $1995 at the door. (Add an extra $300 if you want to attend a special workshop.)

What particularly caught my attention is the following session:

ETHICS OF KOL ENGAGEMENTAchieving the Right Balance between Developing a Positive Working Relationship with KOLs and Ensuring their Ability to Maintain their Professional Independence

Understanding what activities you can reasonably expect to engage KOLs in

Knowing what is appropriate to ask the KOL to assist with and what is over the line

Avoiding ethical conflicts both domestically and internationally through the education and explanation of KOL involvement

Setting a standard of belief’s [sic] about your company and your product with your KOL and communicating this standard to the KOL

Synchronizing work ethics with KOLs and being in harmony through an understanding of the right way and wrong way of working with your KOL

Speaker: Paul Meade, MSc, MPH, President, THOUGHT LEADER SELECT

Of course, I think it is a wonderful thing that people in the drug industry marketing business are concerned about ethics. I am tempted to write Mr. Meade and ask him if he'd like to share any of his ethical insights with the readers of this blog. But somehow I suspect that the answer will be--if I really want to know, where's my $1695?

I don't believe that I have had occasion to mention the interesting group called RUC previously in this blog, so here's some background.

A while back Medicare decided to pay physicians according to an instrument called the resource-based relative value scale (RBRVS). This was originally designed to equalize payment between procedural specialists and primary care type docs by considering how much work physicians actually put into each medical task, rather than simply what past, customary payment had been. It has never worked out that way because the procedural specialists hijacked the mechanisms by which it was implemented, but that's another story. But a committee was needed to update the original payment framework as new procedures were added to the repertoire. Thus came the creation of the RBRVS Update Committee. You'd think that would be called the RBRVSUC, but they took pity on us and shortened that to RUC.

Funny thing, though. The decisions of RUC ultimately control how Medicare pays all physicians in the US, which in turn is often followed by other insurers. So you'd think that RUC would be a government committee and its proceedings would follow open-government practices. But in fact RUC was set up by the AMA, and is officially only an advisory committee to Medicare--though Medicare follows its "advice" 90 percent of the time, and has no alternative mechanism to get similar "advice" from anywhere else. In turn, the AMA has treated RUC in a wholly proprietary fashion, to the extent that even (until recently) the membership list of RUC was effectively kept secret.

RUC is made up mostly of representatives from the various specialty societies. This means that primary care physicians have basically 3 representatives on the panel, from family medicine, internal medicine, and pediatrics. (And since internal medicine and pediatrics number both primary care physicians and specialist physicians among their ranks, you could say their interests are divided.) The procedural specialists have the vast majority of seats. With this voting lineup, you'll be shocked to learn that the RUC has generally proposed physician payments that continue to widen the gap between the low-paid primary care docs and the proceduralists. In recent years, under significant political pressure, RUC has tried to modify this to some extent and has taken some action to narrow the gap just a bit. During these years, the number of US medical graduates seeking careers in primary care has steadily dropped due to the low income, despite the agreement of all health policy mayvins that the US really needs more primary care docs and fewer proceduralists.

Side note--some people like me have wondered why my own group, the American Academy of Family Physicians, keeps on legitimating this charade by attending RUC meetings, when its members' best interests would seem to be served by very publicly walking out and denouncing RUC. But the primary care people seem to have reasoned that even if they only come away with crumbs, sitting at the table is better for us than not being at the table.

OK, so in the past few years some light of publicity has finally been shown on RUC, and there is now at last a "Replace the RUC" movement: http://replacetheruc.org/

Now to the news--our friends over at Health Care Renewal:http://hcrenewal.blogspot.com/2011/04/rucing-about-conflicts-of-interest.html--took advantage of the fact that through all this agitation, the "Replace the RUC" group has finally managed to make public a list of the RUC membership. So the HCR gang did what I usually cannot find the time to do myself, which is Google all those people and make a list of their industry ties. And guess what? It turns out that roughly half of the RUC membership have significant conflicts of interest (which the blog proceeds to list person by person).

In the past the AMA used as one reason not to make the RUC membership list public, that the people might be harrassed and lobbied by those who wanted to affect the structure of the payment system. So now we can see the real worry. It turns out that the industries that have wanted to steer the physician reimbursement system in ways favorable to their profits, have had the desired access to half of the RUC membership all along. The AMA just didn't want the rest of us to have any chance to get our word in.

According to a survey stimulated by the PharmedOut project at Georgetown and AMSA's PharmFree initiative (subscription required to access), family medicine residencies in the US are gradually decreasing their involvement with the pharmaceutical industry.

The survey studied family medicine residencies in 2008 and was hampered by only a 62% response rate. The authors concluded that more than two-thirds of (responding) programs limit industry access to residents in various ways, and one-quarter can be classified as pharm-free--contracting with only 10 percent of residencies that disallowed industry support in 1992. They noted similar trends in internal medicine, where others have noted a drop in industry support of residencies from 89% in 1990 to 56% in 2007. Many respondents noted that the policies in the institutions (medical centers or hospitals) where the residency was located had recently changed and this seems to have prompted changing residency policies as well.

Large academic medical centers have recently taken leadership in developing "pharm-free" policies, so the authors were interested to note that community-based residency programs seemed just as likely to move in a pharm-free direction as those located within academic centers.

One sticking point remains just how one educates residents regarding the pros and cons of dealing with drug marketers. Residencies were not rated as "pharm-free" if they allowed access of drug detailers to residents, even if within the context of offering formal education about how to deal with detailers. Faculty in many residencies insist that residents need this "real world" experience and that faculty present can counter any biased messages conveyed by the detailers. The authors reply that companies would not allow detailers to attend these sessions if they did not believe that a positive message about seeing detailers in the future would be conveyed to residents as a result. The entire discussion section is well worth reading as it addresses a number of similar issues.

Hiltzik addresses the practice of a big drug company whose blockbuster drug is about to go off patent settling with a generic drug company that's challenging the patent in court, essentially paying off the generic company to allow the brand-name company an additional time period of patent protection. (I addessed this in HOOKED as a form of "evergreening"; the term favored more lately is "pay-for-delay.") The big company gets the profits from brand-name sales without generic competition for extra months or even years; the generic company gets cash on the barrelhead without haviong actually to manufacture any drugs; and the consumers get shafted. Frank Baldino, CEO of Cephalon, publicly stated in 2006 that his company was going to land $4B in Provigil revenues over the next six years, by means of paying $200M to several generic companies to get them to back off. One study concluded that extending patent protection on the average drug by one year costs consumers $660M.

Hiltzik notes that the Federal Trade Commission thought it had essentially eliminated pay-for-delay after 1999 by more aggressive enforcement, and a 2003 federal appeals court decision ruled pay-for-delay deals illegal. But since then, other courts have approved selected pay-for-delay deals. Plus a provision to ban these deals got sliced out of the Obama health reform law at the last minute. The net result:

"The number of pay-for-delay deals has soared in recent years. In fiscal 2010, brand and generic drug makers resolved 113 patent disputes, up from 68 the year before. Of those, at least 31 involved payment to the generics firm, up from 19 the year before.The FTC's figures may understate the number of deals involving payment, because the industry is getting more clever at avoiding straight cash payoffs and disguising them as transactions such as licensing, marketing or manufacturing agreements, many of which the agency believes are shams.'Settlements are becoming more sophisticated,' Hemphill [C. Scott Hemphill of Columbia Law School] agrees. When suspect deals are made, he says, the burden of proof should be on the companies to justify them. 'It should be the drug makers' jobs to explain why these payments are innocent rather than the government's job to explain why they're inherently bad.'"Hiltzik begins his column by noting that both the brand-name and the generic drug industries have lately rolled out their big guns in defense of pay-for-delay, arguing that it's really in the public interest. As Hiltzik sagely comments, "When [these two warring factions] land on the same side of an issue it's a good guess that the consumer is getting whacked."

Lung cancer has always been a problem for physicians advocating screening and early detection. For a long time no one was able to show that by the time a lung nodule gets big enough to be seen on an x-ray or a CT scan, that there was anything you could do to save the patient's life or significantly alter the course of the disease. Therefore the various groups that recommend screening tests for cancer did not, as a rule, recommend screening for lung cancer.

At least two powerful groups did not like this. One was the tobacco industry. They wanted to be able to reassure smokers that they could reduce the risk of dying of lung cancer while still puffing away with abandon (and profit to the companies). The other was the big companies like General Electric that make CT scanners and that want to push the use of these expensive devices.

These two groups found some willing scientific collaborators based at Weill Cornell Medical College in New York. Money flowed into the group from the tobacco industry and GE, and they supplemented that cash with some hefty Federal grants. The group made headlines by publishing a paper in 2006 claiming that they could prevent as many as 80 percent of lung cancer deaths with their screening protocol.

Those who knew about the basic epidemiology and biology of lung cancer thought these data too good to be true from the get-go. Their suspicions were deepened when it was revealed in 2008 that the chief scientists had these conflicted relationships with powerful industry groups with a stake in the outcome of the study.

But it gets worse, as it turns out. The sources listed above are based on a review that Weill Cornell conducted, and then apparently never revealed or acted upon. The review did, however, apparently result in the two chief scientists relocating to other institutions.

The major publicity in the past week or so has focused on one easy-to-understand lapse. It turns out that the review team could not locate 90% of the subject consent forms, meaning that in a very basic way, this research failed to meet the criteria for ethical research. The chief investigators made the lame protest that the study was conducted at 37 institutions, and that each center was responsible for maintaining its own set of consent forms. But the fact remains that in publications, the chief authors assured readers that all subjects had given formal consent, and that it now turns out they had no clue as to whether or not consent was obtained.

But a closer reading of The Cancer Letter reveals other basic flaws. Apparently the study protocol failed to assure that uniform standards were followed at all 37 participating centers. Also, no effect size calculation was ever conducted to determine how many subjects needed to be enrolled to prove or disprove the study hypothesis; so essentially this is a never ending study. (And indeed, since the review was sent to Weill Cornell, a further 10,000 subjects have been recruited, which is completely unethical if the basic protocol has been questioned.) In other words, cutting to the chase, as science, this study was a piece of junk--and journals who published data from the study need to seriously consider retracting the articles.

Despite being a piece of junk, the research may have gotten something right. A later study that appears to have been sound, that was Federally funded, concluded that lung cancer screening could be of value in heavy smokers. But while agreeing with the overall direction of the Weill Cornell findings, the Federal study found an effect size much smaller than the 80% claim. (For the reasons I started off with, skeptics might worry that even this Federal study might not be borne out in future research.)

I dare not say if there is any general lesson here about conflicts of interest in research funding. Certainly you can have conflicts of interest and still do research that is scientifically valid and that follows the proper rules of human subjects protection. But in terms of research not passing the sniff test, and then later turning out to smell worse and worse the more you examine it, this group of studies seems to have set the curve.

Thursday, May 5, 2011

A lot of news this past week or so, and I am writing this from an otherwise very lovely hotel in downtown Krakow, Poland that suffers from an agonizingly slow Internet connection; so many updates will have to await my return stateside. However I did want to circulate the link to the new ProPublica investigative reporting piece:

Briefly, the Heart Rhythm Society annual convention is used as a poster child for the incredible amount of industry cash that flows into the coffers of medical specialty societies, and how inadequate are the present reporting structures to find out about this. And of course the specialty societies insist that none of their behavior is in any way influenced by their dependence on industry cash--which they frankly admit they could not figure out a way to do without.

The degree of either naivete or rationalization among the leadership of these organizations is well represented in a statement by Dr. Jack Lewin, CEO of the American College of Cardiology: “I don’t buy a soft drink just because of the advertising… I buy it because I like it.” Just think about this for a minute. The beverage companies, which last time I heard are making tidy profits, have at their beck and call all sorts of sociological and psychological expertise as to what sort of advertising works and what doesn't. Based on that expertise they have chosen to spend millions on advertising. They are obviously betting that the normally constructed human will be influenced by those ads. What arrogance makes the leader of a physician group--and how a gang that is the most blatant docs' union defending above all else its members' high levels of income, could presume to call itself a "college," needs some explaining--imagine that he's so far superior to the rank and file of humanity so as not to be influenced?

The other new (to me) feature of this report is the "tag and release" program as wags have dubbed it. This refers to the industry's ability to purchase the privilege of having tracking devices implanted in the conference badges of attendees, allowing them to exactly track the person's progress through the exhibit hall and meeting, to see just where people go and what booths they visit. (I assume somebody is interested in how often they go to the rest room and exactly what they do there. Don't worry, there's industry advertising posted in the restroom stalls too.)

The take home message here is how these organizations sell their own membershjip to industry as a way to add to their funding potential. I have a request for all medical specialists who read this blog--before you attend a major meeting of your organization, be sure to go on the website that the organization hopes you will not visit, the part aimed at exhibitors, and see how you yourself is being marketed to the drug and device companies as advertising fodder, whose behavior your society more or less promises to deliver over to the industry if only they invest enough funds in supporting the meeting. (And then again these groups have the nerve to call themselves professional societies.) If after that you still can stomach attending the meeting, have a good time and enjoy all the industry freebies.

The other take home messages have to do with first, the continued lack of transparency among these organizations as to how much they take and from whom (the Heart Rhythm Society got targeted, ironically, because they actually became recently more transparent than most others); and second, the almost universal protestation among any would-be reformers among these organizations that the whole problem can easily be solved merely by disclosing all conflicts of interest. (We'll keep on raking in the cash, but we'll just inform you better about it.)